Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.
BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating...
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ftdoajarticles:oai:doaj.org/article:0f7f52847a69419097bde9f4bef6c139 2023-05-15T15:12:14+02:00 Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. Gregory J Crowther Dhanasekaran Shanmugam Santiago J Carmona Maria A Doyle Christiane Hertz-Fowler Matthew Berriman Solomon Nwaka Stuart A Ralph David S Roos Wesley C Van Voorhis Fernán Agüero 2010-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000804 https://doaj.org/article/0f7f52847a69419097bde9f4bef6c139 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2927427?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 doi:10.1371/journal.pntd.0000804 1935-2727 1935-2735 https://doaj.org/article/0f7f52847a69419097bde9f4bef6c139 PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e804 (2010) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2010 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000804 2022-12-31T03:37:35Z BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 4 8 e804 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Gregory J Crowther Dhanasekaran Shanmugam Santiago J Carmona Maria A Doyle Christiane Hertz-Fowler Matthew Berriman Solomon Nwaka Stuart A Ralph David S Roos Wesley C Van Voorhis Fernán Agüero Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can ... |
format |
Article in Journal/Newspaper |
author |
Gregory J Crowther Dhanasekaran Shanmugam Santiago J Carmona Maria A Doyle Christiane Hertz-Fowler Matthew Berriman Solomon Nwaka Stuart A Ralph David S Roos Wesley C Van Voorhis Fernán Agüero |
author_facet |
Gregory J Crowther Dhanasekaran Shanmugam Santiago J Carmona Maria A Doyle Christiane Hertz-Fowler Matthew Berriman Solomon Nwaka Stuart A Ralph David S Roos Wesley C Van Voorhis Fernán Agüero |
author_sort |
Gregory J Crowther |
title |
Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
title_short |
Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
title_full |
Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
title_fullStr |
Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
title_full_unstemmed |
Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
title_sort |
identification of attractive drug targets in neglected-disease pathogens using an in silico approach. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doi.org/10.1371/journal.pntd.0000804 https://doaj.org/article/0f7f52847a69419097bde9f4bef6c139 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e804 (2010) |
op_relation |
http://europepmc.org/articles/PMC2927427?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 doi:10.1371/journal.pntd.0000804 1935-2727 1935-2735 https://doaj.org/article/0f7f52847a69419097bde9f4bef6c139 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000804 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
4 |
container_issue |
8 |
container_start_page |
e804 |
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1766342943728205824 |